Ferroptosis-centered Drug Response Information

General Information of the Drug (ID: ferrodrug0235)
Name
Tiliroside
Synonyms
Tiliroside; 20316-62-5; Tribuloside; Trans-Tiliroside; 15M04TXR9M; CHEMBL266564; [(2R,3S,4S,5R,6S)-6-[5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxochromen-3-yl]oxy-3,4,5-trihydroxyoxan-2-yl]methyl (E)-3-(4-hydroxyphenyl)prop-2-enoate; CHEBI:80944; 22153-44-2; 2-Propenoic acid, 3-(4-hydroxyphenyl)-, 6'-ester with 3-(beta-D-glucopyranosyloxy)-5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one; ((2R,3S,4S,5R,6S)-6-((5,7-Dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl (E)-3-(4-hydroxyphenyl)acrylate; [(2R,3S,4S,5R,6S)-6-[5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-chromen-3-yl]oxy-3,4,5-trihydroxy-tetrahydropyran-2-yl]methyl (E)-3-(4-hydroxyphenyl)prop-2-enoate; UNII-15M04TXR9M; Potengriffioside A; RONACARE TILIROSIDE; TILIROSIDE [INCI]; SCHEMBL23597; Tiliroside, analytical standard; MEGxp0_000169; DTXSID601021936; GLXC-13144; 6''-O-trans-p-Coumaroylastragalin; Kaempferol-3-(p-coumaryl)glucoside; HY-N2443; BDBM50241244; MFCD00017454; AKOS015896718; NCGC00163634-01; ASTRAGALIN-6''-TRANS-P-COUMARATE; MS-30569; CS-0022668; kaempferol 3-O-(6'-O-p-coumaroyl)-glucoside; C17140; A814433; Q-100248; KAEMPFEROL 3-O-(6''-O-P-COUMAROYL)GLUCOSIDE; Q23418844; kaempferol-3-beta-D-(6-O-trans-p-coumaroyl)glucopyranoside; Kaempferol-3-O-(6-O-trans-p-coumaroyl)-.beta.-glucopyranoside; kaempferol-3-O-beta-D-(6''-(E)-p-coumaroyl)-glucopyranoside; 3-O-KAEMPFEROL 6-O-(TRANS-P-COUMAROYL)-.BETA.-D-GLUCOPYRANOSIDE; kaempferol 3-O-(6'''' ''''-O-E-p-coumaroyl)-beta-D-glucopyranoside; KAEMPFEROL 3-O-(6''-O-(E)-P-COUMAROYL)-.BETA.-D-GLUCOPYRANOSIDE; KAEMPFEROL 3-O-.BETA.-D-(6-O-TRANS-P-COUMAROYL)GLUCOPYRANOSIDE; KAEMPFEROL-3-O(-6-O-TRANS-P-COUMAROYL-.BETA.-GLUCOPYRANOSIDE; KAEMPFEROL 3-O-(6''-O-(TRANS-P-COUMAROYL))-.BETA.-D-GLUCOPYRANOSIDE; ((2R,3S,4S,5R,6S)-6-((5,7-Dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl 3-(4-hydroxyphenyl)acrylate; (E)-((2R,3S,4S,5R,6S)-6-(5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-3-yloxy)-3,4,5-trihydroxy-tetrahydro-2H-pyran-2-yl)methyl 3-(4-hydroxyphenyl)acrylate; (E)-((2R,3S,4S,5R,6S)-6-(5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-3-yloxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl 3-(4-hydroxyphenyl)acrylate; 2-PROPENOIC ACID, 3-(4-HYDROXYPHENYL)-, 6'-ESTER WITH 3-(.BETA.-D-GLUCOPYRANOSYLOXY)-5,7-DIHYDROXY-2-(4-HYDROXYPHENYL)-4H-1-BENZOPYRAN-4-ONE, (E)-; 4H-1-BENZOPYRAN-4-ONE, 5,7-DIHYDROXY-2-(4-HYDROXYPHENYL)-3-((6-O-((2E)-3-(4-HYDROXYPHENYL)-1-OXO-2-PROPEN-1-YL)-.BETA.-D-GLUCOPYRANOSYL)OXY)-; 4H-1-Benzopyran-4-one, 5,7-dihydroxy-2-(4-hydroxyphenyl)-3-[[6-O-[(2E)-3-(4-hydroxyphenyl)-1-oxo-2-propenyl]-.beta.-D-glucopyranosyl]oxy]-; 5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4E-1-benzopyran-3-yl 6-O-[(2E)-3-(4-hydroxyphenyl)prop-2-enoyl]-beta-D-glucopyranoside

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Status
Investigative
Drug Type
Small molecular drug
Structure
Formula
C30H26O13
IUPAC Name
[(2R,3S,4S,5R,6S)-6-[5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxochromen-3-yl]oxy-3,4,5-trihydroxyoxan-2-yl]methyl (E)-3-(4-hydroxyphenyl)prop-2-enoate
Canonical SMILES
C1=CC(=CC=C1C=CC(=O)OCC2C(C(C(C(O2)OC3=C(OC4=CC(=CC(=C4C3=O)O)O)C5=CC=C(C=C5)O)O)O)O)O
InChI
InChI=1S/C30H26O13/c31-16-6-1-14(2-7-16)3-10-22(35)40-13-21-24(36)26(38)27(39)30(42-21)43-29-25(37)23-19(34)11-18(33)12-20(23)41-28(29)15-4-8-17(32)9-5-15/h1-12,21,24,26-27,30-34,36,38-39H,13H2/b10-3+/t21-,24-,26+,27-,30+/m1/s1
InChIKey
DVGGLGXQSFURLP-VWMSDXGPSA-N
PubChem CID
5320686
TTD Drug ID
D0IB3K
Full List of Ferroptosis Target Related to This Drug
Nuclear factor erythroid 2-related factor 2 (NFE2L2)
 Target Info 
In total 2 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Responsed Regulator Serine/threonine-protein kinase TBK1 (TBK1) Suppressor
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
Hep 3B2.1-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0326
SMMC-7721 cells Endocervical adenocarcinoma Homo sapiens CVCL_0534
L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
In Vivo Model
All animal studies were approved by the Committee on Ethics of Animal Experiments of Binzhou Medical University (approval no: BZMU-IACUC-2021-331, date: 09/10/2021). To generate the ectopic HCC mouse models, HepG2-luciferase cells (HepG2 cells transfected with luciferase gene) were suspended in serum-free media and matrigel (BD Biosciences) at a ratio of 1:1 v/v. A total of 2.5 x 106 HepG2-luciferase cells/100 ul were injected into the left axilla of mice. After reaching a tumor size of 100-150 mm3, all mice were randomly divided into four groups: control (vehicle, intraperitoneal [i.p.]), tiliroside (20 mg/kg,i.p.), sorafenib (30 mg/kg,i.p.), or combination treatment (tiliroside and sorafenib,i.p.). All treatments were administered every 3 d, and the length and width of tumor were measured every 4 d. The formula tumor volume = (length x width2)/2 was used to calculate the tumor volume. Body weight was recorded every 7 d, and the morphology of the tumor was photographed using animal in vivo imaging technology (IVIS Spectrum; PerkinElmer) before the day of sacrifice. The mice were sacrificed 40 d after administration, and the tumors were dissected and weighed. The major organs and xenograft tumors were fixed with 4% paraformaldehyde.

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Response regulation Tiliroside directly binds to TBK1 and inhibits its activity, which inhibits the phosphorylation of Ser349 on p62. Consequently, this decreases the affinity of p62 for Keap1, promotes ubiquitination and degradation of Nrf2 and ferroptosis, and eventually increases the sensitivity of hepatocellular carcinoma cells to sorafenib.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Responsed Regulator Kelch-like ECH-associated protein 1 (KEAP1) Driver
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
Hep 3B2.1-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0326
SMMC-7721 cells Endocervical adenocarcinoma Homo sapiens CVCL_0534
L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
In Vivo Model
All animal studies were approved by the Committee on Ethics of Animal Experiments of Binzhou Medical University (approval no: BZMU-IACUC-2021-331, date: 09/10/2021). To generate the ectopic HCC mouse models, HepG2-luciferase cells (HepG2 cells transfected with luciferase gene) were suspended in serum-free media and matrigel (BD Biosciences) at a ratio of 1:1 v/v. A total of 2.5 x 106 HepG2-luciferase cells/100 ul were injected into the left axilla of mice. After reaching a tumor size of 100-150 mm3, all mice were randomly divided into four groups: control (vehicle, intraperitoneal [i.p.]), tiliroside (20 mg/kg,i.p.), sorafenib (30 mg/kg,i.p.), or combination treatment (tiliroside and sorafenib,i.p.). All treatments were administered every 3 d, and the length and width of tumor were measured every 4 d. The formula tumor volume = (length x width2)/2 was used to calculate the tumor volume. Body weight was recorded every 7 d, and the morphology of the tumor was photographed using animal in vivo imaging technology (IVIS Spectrum; PerkinElmer) before the day of sacrifice. The mice were sacrificed 40 d after administration, and the tumors were dissected and weighed. The major organs and xenograft tumors were fixed with 4% paraformaldehyde.

    Click to Show/Hide
Response regulation Tiliroside directly binds to TBK1 and inhibits its activity, which inhibits the phosphorylation of Ser349 on p62. Consequently, this decreases the affinity of p62 for Keap1, promotes ubiquitination and degradation of Nrf2 and ferroptosis, and eventually increases the sensitivity of hepatocellular carcinoma cells to sorafenib.
References
Ref 1 Tiliroside targets TBK1 to induce ferroptosis and sensitize hepatocellular carcinoma to sorafenib. Phytomedicine. 2023 Mar;111:154668. doi: 10.1016/j.phymed.2023.154668. Epub 2023 Jan 15.